Loricrin keratoderma is associated with single nucleotide insertion frame-shift mutations in the loricrin gene. These frame-shift mutations result in addition of a nuclear localization signal to the loricrin protein which causes the loricrin to accumulate in the nucleus where it produces actions that are not understood. The outcome is an extremely debilitating disease of epidermal hyperkeratosis, hyperproliferation, parakeratosis, nuclear loricrin accumulation, and pseudoainhum (autoamputation) of the digits. Mouse studies support a role for mutant loricrin in disease pathogenesis as mutant loricrin-expressing mice display disease features. However, how nuclear loricrin influences events and whether nuclear loricrin is absolutely required for disease pathogenesis is not known. Moreover, our knowledge is very limited regarding how cell signaling is altered in keratoderma. We have developed a novel mouse model wherein we inactivate AP1 transcription factor signaling. The remarkable finding is that these mice display a phenotype that matches the human keratoderma phenotype. This includes epidermal hyperproliferation, hyperkeratosis, parakeratosis, nuclear loricrin accumulation, and tail and digit pseudoainhum. The fact that this appears upon inhibition of AP1 transcription factor function in the suprabasal epidermis, strongly suggests a relationship between nuclear loricrin accumulation, reduced AP1 factor signaling and disease pathogenesis. These mice represent an intriguing opportunity to extend previous discoveries to learn how nuclear loricrin may drive the pathology of keratoderma. We propose a novel hypothesis that nuclear accumulation of loricrin in the epidermal suprabasal layers alters AP1 transcription factor signaling in these cells to drive the disease phenotype.